Project Summary Rare inherited disorders provide unique opportunities to identify disease genes in humans, providing insight into disease pathophysiology and often a better understanding of essential biological processes. This can lead to improved diagnosis and treatment of patients with a broad range of disorders. The goal of this proposal is to study the mechanisms underlying familial predisposition to hematological diseases such as myelodysplastic syndrome (MDS) and the myeloproliferative neoplasms (MPN). These malignancies are traditionally thought to occur due to acquired somatic mutations that become more frequent with age. However, a growing body of evidence indicates that a significant number of patients harbor inherited genetic variants that contribute to the onset of the malignant phenotype in adulthood. Understanding the etiology of this process remains an important area of scientific research. Dr. Braunstein is a physician-scientist with a long-standing interest in human genetics. He obtained his PhD in molecular genetics prior to entering clinical fellowship at Johns Hopkins School of Medicine. His research efforts during his fellowship training led to the identification of ERBB3 as a novel candidate predisposition gene in MDS. Upon completion of his fellowship, Dr. Braunstein joined the faculty in the Division of Hematology at Johns Hopkins and initiated a research program to investigate genetic predisposition to hematologic diseases. This grant will support Dr. Braunstein in his path toward becoming an independent investigator and assist him in his goal of serving patients with rare inherited hematologic diseases. Previous work involving investigation of a large family with inherited erythroid MDS revealed a missense mutation in the ERBB3 gene as the predisposing pathological variant. This data led to the premise that mutations in ERBB3, or other ERBB genes, may occur in related diseases such as familial MPN, which comprise approximately 10% of all MPN cases. This hypothesis is supported by the identification of a germline variant in ERBB2 co-segregating with disease in a family with inherited MPN. The overarching hypothesis of this application is that activation of the ERBB3 signaling pathway alters normal hematopoiesis and accelerates clonal progression observed in hematologic malignancies such as MDS and MPN. Aim 1 proposes to analyze the expression and function of the ERBB2 and ERBB3 genes in blood development using both primary hematopoietic cells and an induced pluripotent stem cell (iPSC) model. Genetic modification of these cells will be performed to isolate the role of these genes during hematopoiesis. The goal of Aim 2 is to investigate the role of ERBB2 and ERBB3 in predisposition to MDS and MPN. Targeted sequencing of two patient cohorts thought to be enriched for ERBB pathway mutations will be performed. Further, abnormal ERBB3 signaling in the hematopoietic system will be studied using both a patient-derived iPSC model and a mouse model in order to elucidate the mechanisms underlying clonal progression.